Transplantation of embryonic porcine mesencephalic tissue in patients with PD

Schumacher, James M.; Ellias, S.A.; Palmer, Elliott; Kott, H. Stephen; Dinsmore, Jonathan; Dempsey, Peter K.; Fischman, Alan J.; Thomas, Clayton L.; Feldman, Robert G.; Kassissieh, Samir; Raineri, R.; Manhart, Carolyn J.; Penney, Dana L.; Fink, J. Stephen; Isacson, Ole

doi:10.1212/wnl.54.5.1042

Cited by 241 publications

(107 citation statements)

References 28 publications

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“…This study is in part based on the findings from a recently completed first clinical trial with porcine neural tissue grafted into Parkinson's disease patients. Three of the 12 patients in the first study improved significantly and there were no adverse events related to the use of porcine tissue in these patients [10]. No transmission of porcine endogenous retrovirus (PERV) was detected in any of the transplanted patients [11].…”

Section: Introductionmentioning

confidence: 93%

Simultaneous inhibition of B7 and LFA‐1 signaling prevents rejection of discordant neural xenografts in mice lacking CD40L

Larsson

Corbascio

Widner

et al. 2002

Xenotransplantation

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: Transplantation of embryonic human neural tissue can restore dopamine neurotransmission and improve neurological function in patients with Parkinson's disease. Logistical and ethical factors limit the availability of human embryonic allogeneic tissue. Embryonic xenogeneic neural tissue from porcine donors is an alternative form of donor tissue, but effective immunomodulatory techniques are warranted for neural xenotransplantation to become clinically feasible. We transplanted embryonic porcine ventral mesencephalic tissue into the brains of adult untreated C57BL/6 mice, untreated CD40L‐/–mice and CD40L‐/–mice that received injections of anti‐LFA‐1, CTLA4Ig or both compounds. Double‐treated CD40L‐/–mice had large grafts with high numbers of dopaminergic neurons 4 wk after transplantation. The grafts were completely devoid of lymphocytes, macrophages and activated microglia. Untreated C57BL/6 mice had rejected their grafts. Untreated CD40L‐/–mice and CD40L‐/–mice treated with monotherapy of anti‐LFA‐1 or CTLA4Ig had smaller grafts and more microglial and lymphocytic infiltration than double‐treated CD40L‐/–mice. We conclude that immunomodulation with concomitant inhibition of LFA‐1 and B7 signaling in the perioperative period in CD40L‐/–mice prevented the rejection of discordant neural xenografts. The treatment most likely reduced antigen presenting capacity and interfered with the costimulatory signaling needed for T cell activation to occur.

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Section: Introductionmentioning

confidence: 93%

Simultaneous inhibition of B7 and LFA‐1 signaling prevents rejection of discordant neural xenografts in mice lacking CD40L

Larsson

Corbascio

Widner

et al. 2002

Xenotransplantation

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“…There was no improvement in the group data, but two patients are reported to have 15% improvement in clinical rating scales. 71 One case came to autopsy 7 months after grafting and histologically pig tissue was detected, but only 638 dopaminergic cells were seen, far short of the 80,000-100,000 cells needed for clinical effects. 72 Despite the use of immunosuppression with cyclosporin A, lymphocyte infiltration was also seen in the graft region.…”

Section: Clinical Trials Using Embryonic Porcine Tissuementioning

confidence: 99%

Immune problems in central nervous system cell therapy

Barker¹,

Widner

2004

Neurotherapeutics

168

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Summary:Transplantation of cells and tissues to the mammalian brain and CNS has revived the interest in the immunological status of brain and its response to grafted tissue. The previously held view that the brain was an absolute "immunologically privileged site" allowing indefinite survival without rejection of grafts of cells has proven to be wrong. Thus, the brain should be regarded as a site where immune responses can occur, albeit in a modified form, and under certain circumstances these are as vigorous as those seen in other peripheral sites. Clinical cell transplant trials have now been performed in Parkinson's disease, Huntington's disease, demyelinating diseases, retinal disorders, stroke, epilepsy, and even deafness, and normally are designed as cell replacement strategies, although implantation of genetically modified cells for supplementation of growth factors has also been tried. In addition, some disorders of the CNS for which cell therapies are being considered have an immunological basis, such as multiple sclerosis, which further complicates the situation. Embryonic neural tissue allografted into the CNS of animals and patients with neurodegenerative conditions survives, makes and receives synapses, and ameliorates behavioral deficits. The use of aborted human tissue is logistically and ethically complicated, which has lead to the search for alternative sources of cells, including xenogeneic tissue, genetically modified cells, and stem cells, all of which can and will induce some level of immune reaction. We review some of the immunological factors involved in transplantation of cells to CNS.

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“…Other sources of cells, such as xenogeneic mesencephalic DA neurons, 58 have been considered. However, the clinical trials using intrastriatal transplantation of porcine fetal mesencephalic tissue in patients with PD 59,60 have not provided any evidence of…”

Section: Techniques For Generation Of Standardized Da Neurons In Largmentioning

confidence: 99%